CD73 and Tumor Immunity-CD73 and CTLA-4 combination Blockade in Ovarian Cancer

描述（由申请人提供）：癌症免疫治疗的承诺尚未转化为临床成功，因为在癌症患者中起作用的免疫抑制机制可能会阻断有效的抗肿瘤免疫。因此，要通过免疫治疗根除癌症，必须克服肿瘤诱导的免疫抑制。我们最近已经证明了一种新的肿瘤内在免疫抑制机制，其中肿瘤衍生的CD 73作为胞外酶产生胞外腺苷，其通过腺苷受体（AR）信号传导限制抗肿瘤T细胞免疫以促进肿瘤生长。我们还发现，恶性肿瘤中的CD 73表达与肿瘤浸润效应T细胞的免疫状态差密切相关。我们使用CD 73 siRNA处理的肿瘤细胞和CD 73-/-小鼠的令人兴奋的初步数据表明，肿瘤和宿主CD 73的消融以T细胞依赖性方式协同抑制肿瘤生长。通过使用选择性抑制剂α，β-亚甲基腺苷5 '-二磷酸（APCP）对CD 73进行药理学阻断，观察到了类似的抗肿瘤作用。因此，我们假设肿瘤和宿主CD 73通过它们的酶活性阻止了进入的抗肿瘤T细胞对肿瘤的破坏。在此，我们计划进一步阐明肿瘤保护的机制，即肿瘤细胞或宿主细胞上的CD 73表达影响抗肿瘤T细胞应答。由于内源性抗肿瘤免疫，即使恢复，往往是不够的和短暂的，靶向CD 73癌症治疗可能不是最佳的，除非与其他形式的免疫治疗，如过继性T细胞转移或DC疫苗。将对几种免疫原性肿瘤进行检测，以评估内源性和过继转移的抗肿瘤CD 8 + T细胞免疫与CD 73消融联合治疗的疗效。最后，为了建立靶向CD 73治疗的翻译相关性，我们将探索使用APCP或抗CD 73单克隆抗体（mAb）联合T细胞治疗抑制CD 73的临床前潜力。

DESCRIPTION (provided by applicant): The promises of cancer immunotherapy have not been translated into clinical successes because immune-suppressive mechanisms that act in cancer patients can block effective anti-tumor immunity. Therefore, to eradicate cancers by immunotherapy, tumor-induced immunosuppression must be overcome. We have recently demonstrated a novel tumor-intrinsic immunosuppressive mechanism whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine which limits anti-tumor T cell immunity to promote tumor growth via adenosine receptor (AR) signaling. We also found that CD73 expression in malignant cancers was closely associated with poor immune status of tumor infiltrating effector T cells. Our exciting preliminary data using CD73 siRNA-treated tumor cells and CD73-/- mice indicated that ablation of both tumor and host CD73 synergistically inhibited tumor growth in a T cell-dependent manner. A similar anti-tumor effect was observed by pharmacological blockade of CD73 using the selective inhibitor a,¿-methylene adenosine 5'-diphosphate (APCP). Thus, we hypothesize that both tumor and host CD73 through their enzymatic activity prevent tumor destruction by incoming anti-tumor T cells. We here plan to further clarify the mechanisms of tumor protection by which CD73 expression on either tumor cells or host cells impacts anti-tumor T cell responses. Because endogenous anti-tumor immunity, even if restored, is often insufficient and transient, targeted CD73 cancer therapy may not be optimal unless combined with other forms of immunotherapy, such as adoptive T cell transfer or DC vaccines. Several immunogenic tumors will be tested to assess the efficacy of endogenous and adoptively transferred anti-tumor CD8+ T cell immunity in combination with CD73 ablation. Finally, to establish the translational relevance of targeted CD73 therapy, we will explore the preclinical potential of inhibiting CD73 using APCP or an anti-CD73 monoclonal antibody (mAb) combined with T cell therapy.